Mitochondrial Dysfunction in Lupus T Cells

SLE T cells exhibit both defective AICD and enhanced spontaneous apoptosis (Table 1). Coordinate mitochondrial hyperpolarization and ATP depletion play key roles in abnormal T-cell death of patients with SLE (36), AWm and ROI levels as well as cytoplasmic pH are elevated in patients with SLE in comparison to healthy or controls with rheumatoid arthritis (36,37). Baseline mitochondrial hyperpolarization and ROI levels correlated with diminished GSH levels, suggesting increased utilization of reducing equivalents in patients with SLE.

It is presently unclear whether synthesis of GSH or its regeneration from its oxidized form is deficient in lupus patients. GSH is also required for interleukin-2-dependent T-cell proliferation (45) as well as CD2- and CD3-mediated T-cell activation (46). Thus, a low GSH content may also inhibit CD3-induced H2O2 production. Nevertheless, GSH deficiency predisposes cells for ROI-induced cell death (14,24,47). Diminished H2O2-induced apoptosis of cells with low baseline GSH levels indicates a severe dysfunction of redox signaling in patients with SLE.

Increased ROI production may lead to skewed expression of redox-sensitive surface receptors and lymphokines. As examples, ROIs regulate gene transcription and release of TNF-a and IL-10 (48), both of which are elevated in sera (49,50) and freshly isolated PBLs of patients with SLE (51,52). Expression of TCR Ç-chain is sensitive to oxidative stress (53), and thus increased ROI levels may explain, at least in part, low TCR Ç-chain expression in lupus T cells (54). Cell surface expression of the Fas receptor (55-57) and Fas ligand is also redox sensitive (58). Increased ROI levels may be related to increased IL-10 production, release of FasL, and overexpression of the FasR in SLE (59-61). Elevated NO production may also contribute to increased spontaneous apoptosis (62,63). Mitochondrial ROI production and AWm are early checkpoints in Fas- (15) and H2O2-induced apoptosis (24). Increased ROI levels confer sensitivity to H2O2-, NO-, TNF-a-, or Fas-induced cell death (14). Therefore, elevated baseline ROI and AWm levels may have key roles in enhanced spontaneous death of PBLs in patients with SLE.

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